Systems, assemblies, and methods for treating a bronchial tree

ABSTRACT

Systems, assemblies, and methods to treat pulmonary diseases are used to decrease nervous system input to distal regions of the bronchial tree within the lungs. Treatment systems damage nerve tissue to temporarily or permanently decrease nervous system input. The treatment systems are capable of heating nerve tissue, cooling the nerve tissue, delivering a flowable substance that cause trauma to the nerve tissue, puncturing the nerve tissue, tearing the nerve tissue, cutting the nerve tissue, applying pressure to the nerve tissue, applying ultrasound to the nerve tissue, applying ionizing radiation to the nerve tissue, disrupting cell membranes of nerve tissue with electrical energy, or delivering long acting nerve blocking chemicals to the nerve tissue.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/245,522, now U.S. Pat. No. 8,226,638, filed Sep. 26, 2011, which is acontinuation of U.S. patent application Ser. No. 12/463,304, now U.S.Pat. No. 8,088,127, filed May 8, 2009, which claims the benefit under 35U.S.C. §119(e) of U.S. Provisional Patent Application No. 61/052,082filed May 9, 2008; U.S. Provisional Patent Application No. 61/106,490filed Oct. 17, 2008; and U.S. Provisional Patent Application No.61/155,449 filed Feb. 25, 2009. Each of these applications isincorporated herein by reference in its entirety.

BACKGROUND

1. Technical Field

The present invention generally relates to systems, assemblies, andmethods for treating a bronchial tree, and more particularly, theinvention relates to systems, assemblies, and methods for eliciting adesired response.

2. Description of the Related Art

Pulmonary diseases may cause a wide range of problems that adverselyaffect performance of the lungs. Pulmonary diseases, such as asthma andchronic obstructive pulmonary disease (“COPD”), may lead to increasedairflow resistance in the lungs. Mortality, health-related costs, andthe size of the population having adverse effects due to pulmonarydiseases are all substantial. These diseases often adversely affectquality of life. Symptoms are varied but often include cough;breathlessness; and wheeze. In COPD, for example, breathlessness may benoticed when performing somewhat strenuous activities, such as running,jogging, brisk walking, etc. As the disease progresses, breathlessnessmay be noticed when performing non-strenuous activities, such aswalking. Over time, symptoms of COPD may occur with less and less effortuntil they are present all of the time, thereby severely limiting aperson's ability to accomplish normal tasks.

Pulmonary diseases are often characterized by airway obstructionassociated with blockage of an airway lumen, thickening of an airwaywall, alteration of structures within or around the airway wall, orcombinations thereof. Airway obstruction can significantly decrease theamount of gas exchanged in the lungs resulting in breathlessness.Blockage of an airway lumen can be caused by excessive intraluminalmucus or edema fluid, or both. Thickening of the airway wall may beattributable to excessive contraction of the airway smooth muscle,airway smooth muscle hypertrophy, mucous glands hypertrophy,inflammation, edema, or combinations thereof. Alteration of structuresaround the airway, such as destruction of the lung tissue itself, canlead to a loss of radial traction on the airway wall and subsequentnarrowing of the airway.

Asthma can be characterized by contraction of airway smooth muscle,smooth muscle hypertrophy, excessive mucus production, mucous glandhypertrophy, and/or inflammation and swelling of airways. Theseabnormalities are the result of a complex interplay of localinflammatory cytokines (chemicals released locally by immune cellslocated in or near the airway wall), inhaled irritants (e.g., cold air,smoke, allergens, or other chemicals), systemic hormones (chemicals inthe blood such as the anti-inflammatory cortisol and the stimulantepinephrine), local nervous system input (nerve cells containedcompletely within the airway wall that can produce local reflexstimulation of smooth muscle cells and mucous glands), and the centralnervous system input (nervous system signals from the brain to smoothmuscle cells and mucous glands carried through the vagus nerve). Theseconditions often cause widespread temporary tissue alterations andinitially reversible airflow obstruction that may ultimately lead topermanent tissue alteration and permanent airflow obstruction that makeit difficult for the asthma sufferer to breathe. Asthma can furtherinclude acute episodes or attacks of additional airway narrowing viacontraction of hyper-responsive airway smooth muscle that significantlyincreases airflow resistance. Asthma symptoms include recurrent episodesof breathlessness (e.g., shortness of breath or dyspnea), wheezing,chest tightness, and cough.

Emphysema is a type of COPD often characterized by the alteration oflung tissue surrounding or adjacent to the airways in the lungs.Emphysema can involve destruction of lung tissue (e.g., alveoli tissuesuch as the alveolar sacs) that leads to reduced gas exchange andreduced radial traction applied to the airway wall by the surroundinglung tissue. The destruction of alveoli tissue leaves areas ofemphysematous lung with overly large airspaces that are devoid ofalveolar walls and alveolar capillaries and are thereby ineffective atgas exchange. Air becomes “trapped” in these larger airspaces. This“trapped” air may cause over-inflation of the lung, and in the confinesof the chest restricts the in-flow of oxygen rich air and the properfunction of healthier tissue. This results in significant breathlessnessand may lead to low oxygen levels and high carbon dioxide levels in theblood. This type of lung tissue destruction occurs as part of the normalaging process, even in healthy individuals. Unfortunately, exposure tochemicals or other substances (e.g., tobacco smoke) may significantlyaccelerate the rate of tissue damage or destruction. Breathlessness maybe further increased by airway obstruction. The reduction of radialtraction may cause the airway walls to become “floppy” such that theairway walls partially or fully collapse during exhalation. Anindividual with emphysema may be unable deliver air out of their lungsdue to this airway collapse and airway obstructions during exhalation.

Chronic bronchitis is a type of COPD that can be characterized bycontraction of the airway smooth muscle, smooth muscle hypertrophy,excessive mucus production, mucous gland hypertrophy, and inflammationof airway walls. Like asthma, these abnormalities are the result of acomplex interplay of local inflammatory cytokines, inhaled irritants,systemic hormones, local nervous system, and the central nervous system.Unlike asthma where respiratory obstruction may be largely reversible,the airway obstruction in chronic bronchitis is primarily chronic andpermanent. It is often difficult for a chronic bronchitis sufferer tobreathe because of chronic symptoms of shortness of breath, wheezing,and chest tightness, as well as a mucus producing cough.

Different techniques can be used to assess the severity and progressionof pulmonary diseases. For example, pulmonary function tests, exercisecapacity, and quality of life questionnaires are often used to evaluatesubjects. Pulmonary function tests involve objective and reproduciblemeasures of basic physiologic lung parameters, such as total airflow,lung volume, and gas exchange. Indices of pulmonary function tests usedfor the assessment of obstructive pulmonary diseases include the forcedexpiratory volume in 1 second (FEV1), the forced vital capacity (FVC),the ratio of the FEV1 to FVC, the total lung capacity (TLC), airwayresistance and the testing of arterial blood gases. The FEV1 is thevolume of air a patient can exhale during the first second of a forcefulexhalation which starts with the lungs completely filled with air. TheFEV1 is also the average flow that occurs during the first second of aforceful exhalation. This parameter may be used to evaluate anddetermine the presence and impact of any airway obstruction. The FVC isthe total volume of air a patient can exhale during a forcefulexhalation that starts with the lungs completely filled with air. TheFEV1/FVC is the fraction of all the air that can be exhaled during aforceful exhalation during the first second. An FEV1/FVC ratio less than0.7 after the administration of at least one bronchodilator defines thepresence of COPD. The TLC is the total amount of air within the lungswhen the lungs are completely filled and may increase when air becomestrapped within the lungs of patients with obstructive lung disease.Airway resistance is defined as the pressure gradient between thealveoli and the mouth to the rate of air flow between the alveoli andthe mouth. similarly, resistance of a given airway would be defined asthe ratio of the pressure gradient across the given airway to the flowthrough the airway. Arterial blood gases tests measure the amount ofoxygen and the amount of carbon dioxide in the blood and are the mostdirect method for assessing the ability of the lungs and respiratorysystem to bring oxygen from the air into the blood and to get carbondioxide from the blood out of the body.

Exercise capacity tests are objective and reproducible measures of apatient's ability to perform activities. A six minute walk test (6MWT)is an exercise capacity test in which a patient walks as far as possibleover a flat surface in 6 minutes. Another exercise capacity testinvolves measuring the maximum exercise capacity of a patient. Forexample, a physician can measure the amount of power the patient canproduce while on a cycle ergometer. The patient can breathe 30 percentoxygen and the work load can increase by 5-10 watts every 3 minutes.

Quality of life questionnaires assess a patient's overall health andwell being. The St. George's Respiratory Questionnaire is a quality oflife questionnaire that includes 75 questions designed to measure theimpact of obstructive lung disease on overall health, daily life, andperceived well-being. The efficacy of a treatment for pulmonary diseasescan be evaluated using pulmonary function tests, exercise capacitytests, and/or questionnaires. A treatment program can be modified basedon the results from these tests and/or questionnaires.

Treatments, such as bronchial thermoplasty, involve destroying smoothmuscle tone by ablating the airway wall in a multitude of bronchialbranches within the lung thereby eliminating both smooth muscles andnerves in the airway walls of the lung. The treated airways are unableto respond favorably to inhaled irritants, systemic hormones, and bothlocal and central nervous system input. Unfortunately, this destructionof smooth muscle tone and nerves in the airway wall may thereforeadversely affect lung performance. For example, inhaled irritants, suchas smoke or other noxious substances, normally stimulate lung irritantreceptors to produce coughing and contracting of airway smooth muscle.Elimination of nerves in the airway walls removes both local nervefunction and central nervous input, thereby eliminating the lung'sability to expel noxious substances with a forceful cough. Eliminationof airway smooth muscle tone may eliminate the airways' ability toconstrict, thereby allowing deeper penetration of unwanted substances,such as noxious substances, into the lung.

Additionally, methods of destroying smooth muscle tone by ablatingportions of the airway wall, such as bronchial thermoplasty, often havethe following limitations: 1) inability to affect airways that are notdirectly ablated, typically airways smaller than approximately 3.0 mmwhich may also be narrowed in obstructive lung diseases such as asthma,emphysema, and chronic bronchitis; 2) short-term swelling that causesacute respiratory problems due to perioperative swelling in airwaysalready narrowed by obstructive lung disease effects; 3) hundreds ofapplications to airways within the lungs may be required to alteroverall lung functionality; 4) since multiple generations of airwayswithin the lung are treated (typically generations 2-8), targeting lungairways without missing or over treating specific lung airway sectionscan be problematic; and, 5) separating the treating step into stages maybe required to reduce the healing load on the lung which adds additionalrisk and cost with each additional bronchoscopy treatment session.

Both asthma and COPD are serious diseases with growing numbers ofsufferers. Current management techniques, which include prescriptiondrugs, are neither completely successful nor free from side effects.Additionally, many patients do not comply with their drug prescriptiondosage regiment. Accordingly, it would be desirable to provide atreatment which improves resistance to airflow without the need forpatient compliance.

BRIEF SUMMARY

In some embodiments, a treatment system can be navigated throughairways, such as the right and left main bronchi of the lung root aswell as more distal airways within the lungs, to treat a wide range ofpulmonary symptoms, conditions, and/or diseases, including, withoutlimitation, asthma, COPD, obstructive lung diseases, or other diseasesthat lead to an increased resistance to airflow in the lungs. Thetreatment system can treat one or more target sites without treatingnon-targeted sites. Even if targeted anatomical features (e.g., nerves,glands, membranes, and the like) of main bronchi, lobar bronchi,segmental bronchi or subsegmental bronchi are treated, non-targetedanatomical features can be substantially unaltered. For example, thetreatment system can destroy nerve tissue at target sites withoutdestroying to any significant extent non-targeted tissue that can remainfunctional after performing treatment.

At least some embodiments disclosed herein can be used to affect nervetissue of nerve trunks outside of airway walls while maintaining theairways ability to move (e.g., constrict and/or expand) in response to,for example, inhaled irritants, local nerve stimulation, systemichormones, or combinations thereof. In some embodiments, the nerve tissueof nerve trunks is destroyed without eliminating smooth muscle tone.After damaging the nerve trunks, the airways have at least some muscletone such that the smooth muscles in the airways, if stimulated, canalter the diameter of the airway to help maintain proper lung function.A wide range of different physiological functions associated with smoothmuscle tone can be maintained before, during, and/or after thetreatment.

In some embodiments, a method for treating one or more pulmonarydiseases is provided. The method includes damaging nerve tissue of avagal nerve trunk extending along the outside of a bronchial tree airwayso as to attenuate nervous system signals transmitted to a portion ofthe bronchial tree. The nerve trunk may be the main stem of a nerve,comprising a bundle of nerve fibers bound together by a tough sheath ofconnective tissue. In some embodiments, the nerve tissue is damagedwhile maintaining a functionality of one or more anatomical features,such as blood vessels, also extending alongside the airway so as topreserve a respiratory function of the portion of the bronchial treeafter the nerve tissue is damaged.

Conditions and symptoms associated with pulmonary diseases can bereduced, limited, or substantially eliminated. For example, airwayobstruction can be treated to elicit reduced airflow resistance. Bloodvessels or other tissue can remain intact and functional during and/orafter treatment. The respiratory function that is preserved can includegas exchange, mucociliary transport, and the like. In some embodiments,the nerve tissue, such as nerve tissue of nerve trunks located outsideof the airway, is damaged without damaging to any significant extent aportion of the airway wall that is circumferentially adjacent to thedamaged nerve tissue. Accordingly, non-targeted tissue can besubstantially unaltered by the damage to the airway nerve tissue.

Damaging the nerve tissue can involve delivering energy to the nervetissue such that the destroyed nerve tissue impedes or stops thetransmission of nervous system signals to nerves more distal along thebronchial tree. The nerve tissue can be temporarily or permanentlydamaged by delivering different types of energy to the nerve tissue. Forexample, the nerve tissue can be thermally damaged by increasing atemperature of the nerve tissue to a first temperature (e.g., anablation temperature) while the wall of the airway is at a secondtemperature that is less than the first temperature. In someembodiments, a portion of the airway wall positioned radially inwardfrom the nerve tissue can be at the first temperature so as to preventpermanent damage to the portion of the airway wall. The firsttemperature can be sufficiently high to cause permanent destruction ofthe nerve tissue. In some embodiments, the nerve tissue is part of anerve trunk located in connective tissue outside of the airway wall. Thesmooth muscle and nerve tissue in the airway wall can remain functionalto maintain a desired level of smooth muscle tone. The airway canconstrict/dilate in response to stimulation (e.g., stimulation caused byinhaled irritants, the local nervous system, or systemic hormones). Inother embodiments, the nerve tissue is part of a nerve branch or nervefibers in the airway wall. In yet other embodiments, both nerve tissueof the nerve trunk and nerve tissue of nerve branches/fibers aresimultaneously or sequentially damaged. Various types of activatableelements, such as ablation elements, can be utilized to output theenergy.

In some embodiments, a method for treating a subject comprises moving anelongate assembly along a lumen of an airway of a bronchial tree. Theairway includes a first tubular section, a second tubular section, atreatment site between the first tubular section and the second tubularsection, and a nerve extending along at least the first tubular section,the treatment site, and the second tubular section. The nerve can bewithin or outside of the airway wall. In some embodiments, the nerve isa nerve trunk outside of the airway wall and connected to a vagus nerve.

The method can further include damaging a portion of the nerve at thetreatment site to substantially prevent signals from traveling betweenthe first tubular section and the second tubular section via the nerve.In some embodiments, blood flow between the first tubular section andthe second tubular section can be maintained while damaging a portion ofthe nerve. The continuous blood flow can maintain desired functioning ofdistal lung tissue.

The second tubular section of the airway may dilate in response to thedamage to the nerve. Because nervous system signals are not delivered tosmooth muscle of the airway of the second tubular section, smooth musclecan relax so as to cause dilation of the airway, thereby reducingairflow resistance, even airflow resistance associated with pulmonarydiseases. In some embodiments, nerve tissue can be damaged to causedilation of substantially all the airways distal to the damaged tissue.The nerve can be a nerve trunk, nerve branch, nerve fibers, and/or otheraccessible nerves.

The method, in some embodiments, includes detecting one or oneattributes of an airway and evaluating whether the nerve tissue isdamaged based on the attributes. Evaluating includes comparing measuredattributes of the airway (e.g., comparing measurements taken atdifferent times), comparing measured attributes and stored values (e.g.,reference values), calculating values based on measured attributes,monitoring changes of attributes, combinations thereof, or the like.

In some embodiments, a method for treating a subject includes moving anintraluminal device along a lumen of an airway of a bronchial tree. Aportion of the airway is denervated using the intraluminal device. Insome embodiments, the portion of the airway is denervated withoutirreversibly damaging to any significant extent an inner surface of theairway. In some embodiments, a portion of a bronchial tree is denervatedwithout irreversibly damaging to any significant extent nerve tissue(e.g., nerve tissue of nerve fibers) within the airway walls of thebronchial tree. The inner surface can define the lumen along which theintraluminal device was moved.

The denervating process can be performed without destroying at least oneartery extending along the airway. In some embodiments, substantiallyall of the arteries extending along the airway are preserved during thedenervating process. In some embodiments, one or more nerves embedded inthe wall of the airway can be generally undamaged during the denervatingprocess. The destroyed nerves can be nerve trunks outside of the airway.

In some embodiments, the denervating process can decrease smooth muscletone of the airway to achieve a desired increased airflow into and outof the lung. In some embodiments, the denerving process causes asufficient decrease of smooth muscle tone so as to substantiallyincrease airflow into and out of the lung. For example, the subject mayhave an increase in FEV1 of at least 10% over a baseline FEV1. As such,the subject may experience significant improved lung function whenperforming normal everyday activities, even strenuous activities. Insome embodiments, the decrease of airway smooth muscle tone issufficient to cause an increase of FEV1 in the range of about 10% toabout 30%. Any number of treatment sites can be treated either in themain bronchi, segmental bronchi or subsegmental bronchi to achieve thedesired increase in lung function.

In some embodiments, an elongate assembly for treating a lung is adaptedto damage nerve tissue of a nerve trunk so as to attenuate nervoussystem signals transmitted to a more distal portion of the bronchialtree. The tissue can be damaged while the elongated assembly extendsalong a lumen of the bronchial tree. A delivery assembly can be used toprovide access to the nerve tissue.

In some other embodiments, a system for treating a subject includes anelongate assembly dimensioned to move along a lumen of an airway of abronchial tree. The elongate assembly is adapted to attenuate signalstransmitted by nerve tissue, such as nerve tissue of nerve trunks, whilenot irreversibly damaging to any significant extent an inner surface ofthe airway. The elongate assembly can include an embeddable distal tiphaving at least one actuatable element, such as an ablation element. Theablation element can ablate various types of nerve tissue whenactivated. In some embodiments, the ablation element includes one ormore electrodes operable to output radiofrequency energy.

In some embodiments, a method comprises damaging nerve tissue of a firstmain bronchus to substantially prevent nervous system signals fromtraveling to substantially all distal bronchial branches connected tothe first main bronchus. In some embodiments, most or all of thebronchial branches distal to the first main bronchus are treated. Thenerve tissue, in certain embodiments, is positioned between a tracheaand a lung through which the bronchial branches extend. The methodfurther includes damaging nerve tissue of a second main bronchus tosubstantially prevent nervous system signals from traveling tosubstantially all distal bronchial branches connected to the second mainbronchus. A catheter assembly can be used to damage the nerve tissue ofthe first main bronchus and to damage the nerve tissue of the secondmain bronchus without removing the catheter assembly from a tracheaconnected to the first and second bronchi.

In some embodiments, a method comprises denervating most of a portion ofa bronchial tree to substantially prevent nervous system signals fromtraveling to substantially all bronchial branches of the portion. Incertain embodiments, denervating procedures involve damaging nervetissue using less than about 100 applications of energy, 50 applicationsof energy, 36 applications of energy, 18 applications of energy, 10applications of energy, or 3 applications of energy. Each application ofenergy can be at a different treatment site. In some embodiments,substantially all bronchial branches in one or both lungs are denervatedby the application of energy.

In certain embodiments, one or more detection elements are used todetect attributes of airways before, during, and/or after therapy. Adetection element can physically contact an inner surface of the airwayto evaluate physical properties of the airway. The detection element mayinclude one or more inflatable balloons that can be positioned distal totargeted tissue

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

In the Figures, identical reference numbers identify similar elements oracts.

FIG. 1 is an illustration of lungs, blood vessels, and nerves near toand in the lungs.

FIG. 2A is a schematic view of a treatment system positioned within aleft main bronchus according to one embodiment.

FIG. 2B is a schematic view of a treatment system and an instrumentextending distally from the treatment system.

FIG. 3 is a cross-sectional view of an airway of a bronchial treesurrounding a distal tip of a treatment system positioned along anairway lumen according to one embodiment.

FIG. 4 is a cross-sectional view of an airway of a bronchial treesurrounding a distal tip of a treatment system when smooth muscle of theairway is constricted and mucus is in an airway lumen according to oneembodiment.

FIG. 5A is a partial cross-sectional view of a treatment system having adelivery assembly and an elongate assembly extending through and out ofthe delivery assembly.

FIG. 5B is an illustration of a distal tip of the elongate assembly ofFIG. 5A positioned to affect nerve tissue of a nerve trunk.

FIG. 6 is a side elevational view of a delivery assembly in a lumen of abronchial airway according to one embodiment.

FIG. 7 is a side elevational view of a distal tip of an elongateassembly moving through the delivery assembly of FIG. 6.

FIG. 8 is a side elevational view of the distal tip of the elongateassembly protruding from the delivery assembly according to oneembodiment.

FIG. 9 is an enlarged partial cross-sectional view of the distal tip ofFIG. 8, wherein the distal tip extends into a wall of the airway.

FIG. 10A is a side elevational view of a self-expanding ablationassembly in an airway according to one embodiment.

FIG. 10B is a front view of the ablation assembly of FIG. 10A.

FIG. 11A is a side elevational view of another embodiment of aself-expanding ablation assembly in an airway.

FIG. 11B is a front view of the ablation assembly of FIG. 11A.

FIG. 12A is a partial cross-sectional view of a treatment system havinga delivery assembly and a separate elongate assembly within the deliveryassembly according to one embodiment.

FIG. 12B is a front view of the treatment system of FIG. 12A.

FIG. 13A is a cross-sectional view of a delivery assembly deliveringenergy to a treatment site according to one embodiment.

FIG. 13B is a front view of the delivery assembly of FIG. 13A.

FIG. 14A is a partial cross-sectional view of a treatment system havingan elongate assembly with a port positioned in an airway wall accordingto one embodiment.

FIG. 14B is a front view of the treatment system of FIG. 14A.

FIG. 15A is a side elevational view of a treatment system having anexpandable assembly.

FIG. 15B is a cross-sectional view of the expandable assembly of FIG.15A.

FIG. 16 is a graph of the depth of tissue versus temperature of thetissue.

FIG. 17 is a side elevational view of the expandable assembly of FIG.15A in an airway.

FIG. 18 is a cross-sectional view of the expandable assembly of FIG. 15Aand an airway surrounding the expandable assembly.

FIG. 19A is a side elevational view of a treatment system having anexpandable assembly, in accordance with one embodiment.

FIG. 19B is a cross-sectional view of the expandable assembly of FIG.19A.

FIG. 20A is a side elevational view of a treatment system having anexpandable assembly, in accordance with another embodiment.

FIG. 20B is a cross-sectional view of the expandable assembly of FIG.20A.

FIG. 21 is a cross-sectional view of the expandable assembly of FIG. 20Aand an airway surrounding the expandable assembly.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the art will understand that theinvention may be practiced without these details. In other instances,well-known structures associated with catheter systems, deliveryassemblies, activatable elements, circuitry, and electrodes have notbeen described in detail to avoid unnecessarily obscuring descriptionsof the embodiments of the invention.

Unless the context requires otherwise, throughout the specification andclaims which follow, the word “comprise” and variations thereof, such as“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including but not limited to.”

FIG. 1 illustrates human lungs 10 having a left lung 11 and a right lung12. A trachea 20 extends downwardly from the nose and mouth and dividesinto a left main bronchus 21 and a right main bronchus 22. The left mainbronchus 21 and right main bronchus 22 each branch to form a lobar,segmental bronchi, and sub-segmental bronchi, which have successivelysmaller diameters and shorter lengths in the outward direction (i.e.,the distal direction). A main pulmonary artery 30 originates at a rightventricle of the heart and passes in front of a lung root 24. At thelung root 24, the artery 30 branches into a left and right pulmonaryartery, which in turn branch to form a network of branching bloodvessels. These blood vessels can extend alongside airways of a bronchialtree 27. The bronchial tree 27 includes the left main bronchus 21, theright main bronchus 22, bronchioles, and alveoli. Vagus nerves 41, 42extend alongside the trachea 20 and branch to form nerve trunks 45.

The left and right vagus nerves 41, 42 originate in the brainstem, passthrough the neck, and descend through the chest on either side of thetrachea 20. The vagus nerves 41, 42 spread out into nerve trunks 45 thatinclude the anterior and posterior pulmonary plexuses that wrap aroundthe trachea 20, the left main bronchus 21, and the right main bronchus22. The nerve trunks 45 also extend along and outside of the branchingairways of the bronchial tree 27. Nerve trunks 45 are the main stem of anerve, comprising a bundle of nerve fibers bound together by a toughsheath of connective tissue.

The prime function of the lungs 10 is to exchange oxygen from air intothe blood and to exchange carbon dioxide from the blood to the air. Theprocess of gas exchange begins when oxygen rich air is pulled into thelungs 10. Contraction of the diaphragm and intercostal chest wallmuscles cooperate to decrease the pressure within the chest to cause theoxygen rich air to flow through the airways of the lungs 10. Forexample, air passes through the mouth and nose, the trachea 20, thenthrough the bronchial tree 27. The air is ultimately delivered to thealveolar air sacs for the gas exchange process.

Oxygen poor blood is pumped from the right side of the heart through thepulmonary artery 30 and is ultimately delivered to alveolar capillaries.This oxygen poor blood is rich in carbon dioxide waste. Thinsemi-permeable membranes separate the oxygen poor blood in capillariesfrom the oxygen rich air in the alveoli. These capillaries wrap aroundand extend between the alveoli. Oxygen from the air diffuses through themembranes into the blood, and carbon dioxide from the blood diffusesthrough the membranes to the air in the alveoli. The newly oxygenenriched blood then flows from the alveolar capillaries through thebranching blood vessels of the pulmonary venous system to the heart. Theheart pumps the oxygen rich blood throughout the body. The oxygen spentair in the lung is exhaled when the diaphragm and intercostal musclesrelax and the lungs and chest wall elastically return to the normalrelaxed states. In this manner, air can flow through the branchingbronchioles, the bronchi 21, 22, and the trachea 20 and is ultimatelyexpelled through the mouth and nose.

A treatment system 198 of FIG. 2A can be used to treat the lungs 10 toadjust air flow during expiration or inhalation, or both. For example,airways can be enlarged (e.g., dilated) to decrease air flow resistanceto increase gas exchange. The treatment system 198 can affect nervetissue, such as nerve tissue of a nerve trunk, to dilate airways.

In some embodiments, the treatment system 198 targets the nervous systemwhich provides communication between the brain and the lungs 10 usingelectrical and chemical signals. A network of nerve tissue of theautonomic nervous system senses and regulates activity of therespiratory system and the vasculature system. Nerve tissue includesfibers that use chemical and electrical signals to transmit sensory andmotor information from one body part to another. For example, the nervetissue can transmit motor information in the form of nervous systeminput, such as a signal that causes contraction of muscles or otherresponses. The fibers can be made up of neurons. The nerve tissue can besurrounded by connective tissue, i.e., epineurium. The autonomic nervoussystem includes a sympathetic system and a parasympathetic system. Thesympathetic nervous system is largely involved in “excitatory” functionsduring periods of stress. The parasympathetic nervous system is largelyinvolved in “vegetative” functions during periods of energyconservation. The sympathetic and parasympathetic nervous systems aresimultaneously active and generally have reciprocal effects on organsystems. While innervation of the blood vessels originates from bothsystems, innervation of the airways are largely parasympathetic innature and travel between the lung and the brain in the right vagusnerve 42 and the left vagus nerve 41.

The treatment system 198 can perform any number of procedures on one ormore of these nerve trunks 45 to affect the portion of the lungassociated with those nerve trunks. Because some of the nerve tissue inthe network of nerve trunks 45 coalesce into other nerves (e.g., nervesconnected to the esophagus, nerves though the chest and into theabdomen, and the like), the treatment system 198 can treat specificsites to minimize, limit, or substantially eliminate unwanted damage ofthose other nerves. Some fibers of anterior and posterior pulmonaryplexuses coalesce into small nerve trunks which extend along the outersurfaces of the trachea 20 and the branching bronchi and bronchioles asthey travel outward into the lungs 10. Along the branching bronchi,these small nerve trunks continually ramify with each other and sendfibers into the walls of the airways, as discussed in connection withFIGS. 3 and 4.

The treatment system 198 can affect specific nerve tissue, such as vagusnerve tissue, associated with particular sites of interest. Vagus nervetissue includes efferent fibers and afferent fibers oriented parallel toone another within a nerve branch. The efferent nerve tissue transmitssignals from the brain to airway effector cells, mostly airway smoothmuscle cells and mucus producing cells. The afferent nerve tissuetransmits signals from airway sensory receptors, which respond variouslyto irritants and stretch, to the brain. While efferent nerve tissueinnervates smooth muscle cells all the way from the trachea 20 to theterminal bronchioles, the afferent fiber innervation is largely limitedto the trachea 20 and larger bronchi. There is a constant, baselinetonic activity of the efferent vagus nerve tissues to the airways whichcauses a baseline level of smooth muscle contraction and mucoussecretion.

The treatment system 198 can affect the efferent and/or the afferenttissues to control airway smooth muscle (e.g., innervate smooth muscle)and mucous secretion. The contraction of airway smooth muscle and excessmucous secretion associated with pulmonary diseases often results inrelatively high air flow resistance causing reduced gas exchange anddecreased lung performance.

For example, the treatment system 198 can attenuate the transmission ofsignals traveling along the vagus nerves 41, 42 that cause musclecontractions, mucus production, and the like. Attenuation can include,without limitation, hindering, limiting, blocking, and/or interruptingthe transmission of signals. For example, the attenuation can includedecreasing signal amplitude of nerve signals or weakening thetransmission of nerve signals. Decreasing or stopping nervous systeminput to distal airways can alter airway smooth muscle tone, airwaymucus production, airway inflammation, and the like, thereby controllingairflow into and out of the lungs 10. In some embodiments, the nervoussystem input can be decreased to correspondingly decrease airway smoothmuscle tone. In some embodiments, the airway mucus production can bedecreased a sufficient amount to cause a substantial decrease incoughing and/or in airflow resistance. Signal attenuation may allow thesmooth muscles to relax and prevent, limit, or substantially eliminatemucus production by mucous producing cells. In this manner, healthyand/or diseased airways can be altered to adjust lung function. Aftertreatment, various types of questionnaires or tests can be used toassess the subject's response to the treatment. If needed or desired,additional procedures can be performed to reduce the frequency ofcoughing, decrease breathlessness, decrease wheezing, and the like.

Main bronchi 21, 22 (i.e., airway generation 1) of FIG. 1 can be treatedto affect distal portions of the bronchial tree 27. In some embodiments,the left and right main bronchi 21, 22 are treated at locations alongthe left and right lung roots 24 and outside of the left and right lungs11, 12. Treatment sites can be distal to where vagus nerve branchesconnect to the trachea and the main bronchi 21, 22 and proximal to thelungs 11, 12. A single treatment session involving two therapyapplications can be used to treat most of or the entire bronchial tree27. Substantially all of the bronchial branches extending into the lungs11, 12 may be affected to provide a high level of therapeuticeffectiveness. Because the bronchial arteries in the main bronchi 21, 22have relatively large diameters and high heat sinking capacities, thebronchial arteries may be protected from unintended damage due to thetreatment.

In some embodiments, one of the left and right main bronchi 21, 22 istreated to treat one side of the bronchial tree 27. The other mainbronchus 21, 22 can be treated based on the effectiveness of the firsttreatment. For example, the left main bronchus 21 can be treated totreat the left lung 11. The right main bronchus 22 can be treated totreat the right lung 12. In some embodiments, a single treatment systemcan damage the nerve tissue of one of the bronchi 21, 22 and can damagethe nerve tissue of the other main bronchus 21, 22 without removing thetreatment system from the trachea 20. Nerve tissue positioned along themain bronchi 21, 22 can thus be damaged without removing the treatmentsystem from the trachea 20. In some embodiments, a single procedure canbe performed to conveniently treat substantially all, or at least asignificant portion (e.g., at least 50%, 70%, 80%, 90% of the bronchialairways), of the patient's bronchial tree. In other procedures, thetreatment system can be removed from the patient after treating one ofthe lungs 11, 12. If needed, the other lung 11, 12 can be treated in asubsequent procedure.

The treatment system 198 of FIGS. 2A and 2B can treat airways that aredistal to the main bronchi 21, 22. For example, the treatment system 198can be positioned in higher generation airways (e.g., airwaygenerations>2) to affect remote distal portions of the bronchial tree27. The treatment system 198 can be navigated through tortuous airwaysto perform a wide range of different procedures, such as, for example,denervation of a portion of a lobe, an entire lobe, multiple lobes, orone lung or both lungs. In some embodiments, the lobar bronchi aretreated to denervate lung lobes. For example, one or more treatmentsites along a lobar bronchus may be targeted to denervate an entire lobeconnected to that lobar bronchus. Left lobar bronchi can be treated toaffect the left superior lobe and/or the left inferior lobe. Right lobarbronchi can be treated to affect the right superior lobe, the rightmiddle lobe, and/or the right inferior lobe. Lobes can be treatedconcurrently or sequentially. In some embodiments, a physician can treatone lobe. Based on the effectiveness of the treatment, the physician canconcurrently or sequentially treat additional lobe(s). In this manner,different isolated regions of the bronchial tree can be treated.

The treatment system 198 can also be used in segmental or subsegmentalbronchi. Each segmental bronchus may be treated by delivering energy toa single treatment site along each segmental bronchus. For example,energy can be delivered to each segmental bronchus of the right lung. Insome procedures, ten applications of energy can treat most of orsubstantially all of the right lung. In some procedures, most orsubstantially all of both lungs are treated using less than thirty-sixdifferent applications of energy. Depending on the anatomical structureof the bronchial tree, segmental bronchi can often be denervated usingone or two applications of energy.

The treatment system 198 can affect nerve tissue while maintainingfunction of other tissue or anatomical features, such as the mucousglands, cilia, smooth muscle, body vessels (e.g., blood vessels), andthe like. Nerve tissue includes nerve cells, nerve fibers, dendrites,and supporting tissue, such as neuroglia. Nerve cells transmitelectrical impulses, and nerve fibers are prolonged axons that conductthe impulses. The electrical impulses are converted to chemical signalsto communicate with effector cells or other nerve cells. By way ofexample, the treatment system 198 is capable of denervating a portion ofan airway of the bronchial tree 27 to attenuate one or more nervoussystem signals transmitted by nerve tissue. Denervating can includedamaging all of the nerve tissue of a section of a nerve trunk along anairway to stop substantially all of the signals from traveling throughthe damaged section of the nerve trunk to more distal locations alongthe bronchial tree. If a plurality of nerve trunks extends along theairway, each nerve trunk can be damaged. As such, the nerve supply alonga section of the bronchial tree can be cut off. When the signals are cutoff, the distal airway smooth muscle can relax leading to airwaydilation. This airway dilation reduces airflow resistance so as toincrease gas exchange in the lungs 10, thereby reducing, limiting, orsubstantially eliminating one or more symptoms, such as breathlessness,wheezing, chest tightness, and the like. Tissue surrounding or adjacentto the targeted nerve tissue may be affected but not permanentlydamaged. In some embodiments, for example, the bronchial blood vesselsalong the treated airway can deliver a similar amount of blood tobronchial wall tissues and the pulmonary blood vessels along the treatedairway can deliver a similar amount of blood to the alveolar sacs at thedistal regions of the bronchial tree 27 before and after treatment.These blood vessels can continue to transport blood to maintainsufficient gas exchange. In some embodiments, airway smooth muscle isnot damaged to a significant extent. For example, a relatively smallsection of smooth muscle in an airway wall which does not appreciablyimpact respiratory function may be reversibly altered. If energy is usedto destroy the nerve tissue outside of the airways, a therapeuticallyeffective amount of energy does not reach a significant portion of thenon-targeted smooth muscle tissue.

The treatment system 198 of FIG. 2A includes a treatment controller 202and an intraluminal elongate assembly 200 connected to the controller202. The elongate assembly 200 can be inserted into the trachea 20 andnavigated into and through the bronchial tree 27 with or withoututilizing a delivery assembly. The elongate assembly 200 includes adistal tip 203 capable of selectively affecting tissue.

The controller 202 of FIG. 2A can include one or more processors,microprocessors, digital signal processors (DSPs), field programmablegate arrays (FPGA), and/or application-specific integrated circuits(ASICs), memory devices, buses, power sources, and the like. Forexample, the controller 202 can include a processor in communicationwith one or more memory devices. Buses can link an internal or externalpower supply to the processor. The memories may take a variety of forms,including, for example, one or more buffers, registers, random accessmemories (RAMs), and/or read only memories (ROMs). The controller 202may also include a display, such as a screen.

In some embodiments, the controller 202 has a closed loop system or anopen loop system. For example, the controller 202 can have a closed loopsystem, whereby the power to the distal tip 203 is controlled based uponfeedback signals from one or more sensors configured to transmit (orsend) one or more signals indicative of one or more tissuecharacteristics, energy distribution, tissue temperature, or any othermeasurable parameters of interest. Based on those readings, thecontroller 202 can then adjust operation of the distal tip 203.Alternatively, the treatment system 198 can be an open loop systemwherein the operation of the distal tip 203 is set by user input. Forexample, the treatment system 198 may be set to a fixed power mode. Itis contemplated that the treatment system 198 can be repeatedly switchedbetween a closed loop system and an open loop system to treat differenttypes of sites.

The distal tip 203 of FIGS. 2A-4 can target various sites in the lungs10, including, without limitation, nerve tissue (e.g., tissue of thevagus nerves 41, 42, nerve trunks 45, etc.), fibrous tissue, diseased orabnormal tissues (e.g., cancerous tissue, inflamed tissue, and thelike), muscle tissue, blood, blood vessels, anatomical features (e.g.,membranes, glands, cilia, and the like), or other sites of interest.Various types of distal tips are discussed in connection with FIGS.5A-14B.

FIG. 3 is a transverse cross-sectional view of a healthy airway 100,illustrated as a bronchial tube. The distal tip 203 is positioned alonga lumen 101 defined by an inner surface 102 of the airway 100. Theillustrated inner surface 102 is defined by a folded layer of epithelium110 surrounded by stroma 112 a. A layer of smooth muscle tissue 114surrounds the stroma 112 a. A layer of stroma 112 b is between themuscle tissue 114 and connective tissue 124. Mucous glands 116,cartilage plates 118, blood vessels 120, and nerve fibers 122 are withinthe stroma layer 112 b. Bronchial artery branches 130 and nerve trunks45 are exterior to a wall 103 of the airway 100. The illustratedarteries 130 and nerve trunks 45 are within the connective tissue 124surrounding the airway wall 103 and can be oriented generally parallelto the airway 100. In FIG. 1, for example, the nerve trunks 45 originatefrom the vagus nerves 41, 42 and extend along the airway 100 towards theair sacs. The nerve fibers 122 are in the airway wall 103 and extendfrom the nerve trunks 45 to the muscle tissue 114. Nervous systemsignals are transmitted from the nerve trunks 45 to the muscle 114 viathe nerve fibers 122.

The distal tip 203 of FIG. 3 can damage, excite, or otherwise elicit adesired response of the cilia along the epithelium 110 in order tocontrol (e.g., increase or decrease) mucociliary transport. Manyparticles are inhaled as a person breathes, and the airways function asa filter to remove the particles from the air. The mucociliary transportsystem functions as a self-cleaning mechanism for all the airwaysthroughout the lungs 10. The mucociliary transport is a primary methodfor mucus clearance from distal portions of the lungs 10, therebyserving as a primary immune barrier for the lungs 10. For example, theinner surface 102 of FIG. 3 can be covered with cilia and coated withmucus. As part of the mucociliary transport system, the mucus entrapsmany inhaled particles (e.g., unwanted contaminates such as tobaccosmoke) and moves these particles towards the larynx. The ciliary beat ofcilia moves a continuous carpet of mucus and entrapped particles fromthe distal portions of the lungs 10 past the larynx and to the pharynxfor expulsion from the respiratory system. The distal tip 203 can damagethe cilia to decrease mucociliary transport or excite the cilia toincrease mucociliary transport.

In some embodiments, the distal tip 203 selectively treats targetedtreatment sites inside of the airway wall 103 (e.g., anatomical featuresin the stromas 112 a, 112 b). For example, the mucous glands 116 can bedamaged to reduce mucus production a sufficient amount to prevent theaccumulation of mucus that causes increased air flow resistance whilepreserving enough mucus production to maintain effective mucociliarytransport, if needed or desired. In some embodiments, for example, thedistal tip 203 outputs ablative energy that travels through the innerperiphery of the airway wall 103 to the mucous glands 116. In otherembodiments, the distal tip 203 is inserted into the airway wall 103 toposition the distal tip 203 next to the mucous glands 116. The embeddeddistal tip 203 then treats the mucous glands 116 while limitingtreatment of surrounding tissue. The distal tip 203 can also be used todestroy nerve branches/fibers passing through the airway wall 103 orother anatomical features in the airway wall 103.

If the airway 100 is overly constricted, the air flow resistance of theairway 100 may be relatively high. The distal tip 203 can relax themuscle tissue 114 to dilate the airway 100 to reduce air flowresistance, thereby allowing more air to reach the alveolar sacs for thegas exchange process. Various airways of the bronchial tree 47 may havemuscles that are constricted in response to signals traveling throughthe nerve trunks 45. The tip 203 can damage sites throughout the lungs10 to dilate constricted airways.

FIG. 4 is a transverse cross-sectional view of a portion of the airway100 that has smooth muscle tissue 114 in a contracted state and mucus150 from hypertrophied mucous glands 116. The contracted muscle tissue114 and mucus 150 cooperate to partially obstruct the lumen 101. Thedistal tip 203 can relax the smooth muscle tissue 114 and reduce, limit,or substantially eliminate mucus production of the mucous glands 116.The airway 100 may then dilate and the amount of mucus 150 may bereduced, to effectively enlarge the lumen 101.

The distal tip 203 of FIGS. 3 and 4 can deliver different types ofenergy. As used herein, the term “energy” is broadly construed toinclude, without limitation, thermal energy, cryogenic energy (e.g.,cooling energy), electrical energy, acoustic energy (e.g., ultrasonicenergy), radio frequency energy, pulsed high voltage energy, mechanicalenergy, ionizing radiation, optical energy (e.g., light energy), andcombinations thereof, as well as other types of energy suitable fortreating tissue. By way of example, thermal energy can be used to heattissue. Mechanical energy can be used to puncture, tear, cut, crush, orotherwise physically damage tissue. In some embodiments, the distal tip203 applies pressure to tissue in order to temporarily or permanentlydamage tissue. Electrical energy is particularly well suited fordamaging cell membranes, such as the cell membranes of nerve trunktissue or other targeted anatomical features. Acoustic energy can beemitted as continuous or pulsed waves, depending on the parameters of aparticular application. Additionally, acoustic energy can be emitted inwaveforms having various shapes, such as sinusoidal waves, trianglewaves, square waves, or other wave forms.

In some embodiments, a fluid (e.g., a liquid, gas, or mixtures thereof)is employed to damage tissue. The distal tip 203 can include one or moreflow elements through which the fluid can circulate to control thesurface temperature of the flow element. The flow element can be one ormore balloons, expandable members, and the like. The fluid can beheated/cooled saline, cryogenic fluids, and the like. Additionally oralternatively, the distal tip 203 can include one or more ports throughwhich fluid flows to traumatize tissue.

In some embodiments, the distal tip 203 delivers one or more substances(e.g., radioactive seeds, radioactive materials, etc.), treatmentagents, and the like. Exemplary non-limiting treatment agents include,without limitation, one or more antibiotics, anti-inflammatory agents,pharmaceutically active substances, bronchoconstrictors, bronchodilators(e.g., beta-adrenergic agonists, anticholinergics, etc.), nerve blockingdrugs, photoreactive agents, or combinations thereof. For example, longacting or short acting nerve blocking drugs (e.g., anticholinergics) canbe delivered to the nerve tissue to temporarily or permanently attenuatesignal transmission. Substances can also be delivered directly to thenerves 122 or the nerve trunks 45, or both, to chemically damage thenerve tissue.

FIGS. 5A-14B illustrate embodiments for delivery along a lumen of anairway. The illustrated embodiments are just some examples of the typesof treatment systems capable of performing particular procedures. Itshould be recognized that each of the treatment systems described hereincan be modified to treat tissue at different locations, depending on thetreatment to be performed. Treatment can be performed in airways thatare either inside or outside of the left and right lungs. FIGS. 5A-13Billustrate treatment systems capable of outputting energy. Thesetreatment systems may continuously output energy for a predeterminedperiod of time while remaining stationary. Alternatively, the treatmentsystems may be pulsed, may be activated multiple times, or may beactuated in a combination of any of these ways. Different energyapplication patterns can be achieved by configuring the treatment systemitself or may involve moving the treatment assembly or any of itscomponents to different locations.

Referring to FIG. 5A, a treatment system 198A includes an elongateassembly 200A that has a distal tip 203A positioned along the airway100. The elongate assembly 200A extends through a working lumen 401 of adelivery assembly 400 and includes a flexible shaft 500 and a deployableablation assembly 520 protruding from the shaft 500.

The shaft 500 can be a generally straight shaft that is bent as it movesalong the lumen 401. In some embodiments, the shaft 500 has a preformednon-linear section 503 to direct the ablation assembly 520 towards theairway wall 103. As shown in FIG. 5A, the lumen 401 can have a diameterthat is significantly larger than the outer diameter of the shaft 500.When the shaft 500 passes out of the delivery assembly 400, the shaft500 assumes the preset configuration. The flexible shaft 500 can bemade, in whole or in part, of one or more metals, alloys (e.g., steelalloys such as stainless steel), plastics, polymers, and combinationsthereof, as well as other biocompatible materials.

In some embodiments, the shaft 500 selectively moves between a deliveryconfiguration and a treatment configuration. For example, the shaft 500can have a substantially straight configuration for delivery and acurved configuration for engaging tissue. In such embodiments, the shaft500 can be made, in whole or in part, of one or more shape memorymaterials, which move the shaft 500 between the delivery configurationand the treatment configuration when activated. Shape memory materialsinclude, for example, shape memory alloys (e.g., NiTi), shape memorypolymers, ferromagnetic materials, and the like. These materials can betransformed from a first preset configuration to a second presetconfiguration when activated (e.g., thermally activated).

The ablation assembly 520 includes a protective section 524 and anablation element 525. When the ablation element 525 is activated, theablation element 525 outputs energy to targeted tissue. The protectivesection 524 inhibits or blocks the outputted energy to protectnon-targeted tissue. The ablation element 525 and the protective section524 thus cooperate to provide localized delivery of energy to minimize,limit, or substantially eliminate unwanted ancillary trauma associatedwith the outputted energy.

The ablation element 525 can be adapted to output energy that ablatestissue. The terms “ablate” or “ablation,” including derivatives thereof,include, without limitation, substantial altering of electricalproperties, mechanical properties, chemical properties, or otherproperties of tissue. In the context of pulmonary ablation applicationsshown and described with reference to the variations of the illustrativeembodiments herein, “ablation” includes sufficiently altering of nervetissue properties to substantially block transmission of electricalsignals through the ablated nerve tissue.

The term “element” within the context of “ablation element” includes adiscrete element, such as an electrode, or a plurality of discreteelements, such as a plurality of spaced apart electrodes, which arepositioned so as to collectively treat a region of tissue or treatdiscrete sites. One type of ablation element emits energy that ablatestissue when the element is coupled to and energized by an energy source.Example energy emitting ablation elements include, without limitation,electrode elements coupleable to direct current (“DC”) sources oralternating current (“AC”) sources (e.g., radiofrequency (“RF”) currentsources), antenna elements energizable by microwave energy sources,pulsed high voltage sources, heating elements (e.g., metallic elementsor other thermal conductors which are energized to emit heat viaconvective heat transfer, conductive heat transfer, etc.), lightemitting elements (e.g., fiber optics capable of transmitting lightsufficient to ablate tissue when the fiber optics are coupled to a lightsource), light sources (e.g., lasers, light emitting diodes, etc.),ultrasonic elements such as ultrasound elements adapted to emitultrasonic sound waves sufficient to ablate tissue when coupled tosuitable excitation sources), combinations thereof, and the like.

As used herein, the term “ablate,” including variations thereof, isconstrued to include, without limitation, to destroy or to permanentlydamage, injure, or traumatize tissue. For example, ablation may includelocalized tissue destruction, cell lysis, cell size reduction, necrosis,or combinations thereof.

In some embodiments, the ablation assembly 520 can be connected to anenergy generator (e.g., a radiofrequency (RF) electrical generator) byelectrical cables within the shaft 500. For example, the RF electricalgenerator can be incorporated into the controller 202 of FIG. 2A. Insome embodiments, the RF electrical generator is incorporated into theablation assembly 520.

RF energy can be outputted at a desired frequency based on thetreatment. Example frequencies include, without limitation, frequenciesin the range of about 50 KHZ to about 1000 MHZ. When the RF energy isdirected into tissue, the energy is converted within the tissue intoheat causing the temperature of the tissue to be in the range of about40° C. to about 99° C. The RF energy can be applied for a length of timein the range of about 1 second to about 120 seconds. In someembodiments, the RF generator has a single channel and deliversapproximately 1 to 25 watts of RF energy and possesses continuous flowcapability. Other ranges of frequencies, time internals, and poweroutputs can also be used.

The protective section 524 can be in the form of a shield made, in wholeor in part, of a material that is non-transmissive with respect to theenergy from the ablation element 525. In some embodiments, theprotective section 524 is comprised of one or more metals, opticallyopaque materials, and the like. If the ablation element 525 outputsablative energy, the protective section 524 can block a sufficientamount of the ablative energy to prevent ablation of tissue directlynext to the protective section 524. In this manner, non-targeted tissueis not permanently damaged.

A user can visually inspect the airway 100 using the delivery assembly400 of FIGS. 5A and 5B to locate and evaluate the treatment site(s) andnon-targeted tissues before, during, and/or after performing a therapy.The delivery assembly 400 can be a catheter, delivery sheath,bronchoscope, endoscope, or other suitable device for guiding theelongate assembly 200A. In some embodiments, the delivery assembly 400includes one or more viewing devices, such as optical viewing devices(e.g., cameras), optical trains (e.g., a set of lens), and the like. Forexample, the delivery assembly 400 can be in the form of a bronchoscopehaving one or more lights for illumination and optical fibers fortransmitting images. By way of another example, the delivery assembly400 can have an ultrasound viewing device, as discussed in connectionwith FIGS. 11A and 11B.

FIGS. 6-9 show one exemplary method of using the treatment system 198A.Generally, the treatment system 198A can alter nerve tissue of theairway 100 to control nervous system input to a portion of the lungwhile not damaging to any significant extent other pulmonary structures.

As shown in FIG. 6, the delivery assembly 400 is moved along the lumen101 of the airway 100, as indicated by an arrow 560. The elongateassembly 200A is carried in the delivery assembly 400 to prevent injuryto the airway 100 during positioning of the delivery assembly 400.

FIG. 7 shows the elongate assembly 200A moving along the lumen 401towards an opening 564, as indicated by an arrow 568. While the elongateassembly 200A is moved through the delivery assembly 400 (shown incross-section), the ablation assembly 520 (shown in phantom) can behoused within the shaft 500 to prevent damage to the airway 100 or thedelivery assembly 400, or both. A user can push the shaft 500 out of thedelivery assembly 400 towards the airway wall 103.

FIG. 8 shows a distal end 570 of the shaft 500 proximate to the wall103. The sharp ablation assembly 520 is deployed from the shaft 500 andcontacts the wall 103. The ablation assembly 520 is then advancedthrough the wall 103 until the exposed ablation element 525 is embeddedwithin the wall 103, as shown in FIG. 9. The position of the ablationassembly 520 relative to the airway wall 103 can be adjusted byextending or retracting the ablation assembly 520. Because the ablationassembly 520 is relatively slender, the wall 103 can experience aninsignificant amount of trauma.

The illustrated ablation assembly 520 is connected to one lead of the RFgenerator and the other lead of the RF generator may be connected to anexternal electrode. When the RF generator is activated, the ablationelement 525 delivers RF energy to tissue contacting or adjacent to theablation element 525. RF energy flows through the tissue and isconverted into heat. The heat can be concentrated in the outer portionof the airway wall 103. For example, the ablation element 525 of FIG. 5Boutputs RF energy that causes damage to the nerve trunks 45. In someembodiments, a sufficient amount of RF energy is delivered to the nervetrunk 45 to destroy an entire longitudinal section of the nerve trunk 45while keeping the amount energy that reaches the blood vessels 130 belowan amount that causes tissue destruction. Damage to other non-targetedregions (e.g., the epithelium) can also be kept at or below anacceptable level. Thus, therapies can be performed without damaging toany significant extent other regions of the airway 100, even regionsthat are adjacent to the treatment site.

Natural body functions can help prevent, reduce, or limit damage totissue. If the bronchial artery branches 130 are heated by the treatmentsystem 198A, blood within the blood vessels 130 can absorb the thermalenergy and can then carry the thermal energy away from the heatedsection of the branches 130. In this manner, thermal energy istransferred to the blood. After the treatment is performed, thebronchial artery branches 130 can continue to maintain the health oflung tissue.

This procedure may be repeated to damage additional tissue of nervetrunks 45 located outside the circumference of the wall 103. In someembodiments, all the nerves about the airway 100 can be treated toprevent signals from passing between a proximal section 571 of theairway 100 and distal section 573 of the airway 100, as shown in FIG.5A. Because signals are not transmitted to the distal section 573, thedistal section 573 can dilate. The airway 100 can also remain generallyintact to maintain the health of the distal section 573. Upon completionof the treatment process, the ablation assembly 520 is retracted backinto the shaft 500 for removal from the airway 100 or for placement atother treatment locations.

Treatment efficacy can be evaluated based at least in part on one ormore airway attributes, pulmonary function tests, exercise capacitytests, and/or questionnaires. Patients can be evaluated to track andmonitor their progress. If needed or desired, additional procedures canbe performed until desired responses are achieved.

Different types of instruments for evaluating airway attributes may beused with treatment systems. During ablation, feedback from aninstrument can indicate whether the targeted tissue has been ablated.Once targeted tissue is ablated, therapy can be discontinued to minimizeor limit collateral damage, if any, to healthy untargeted tissue. FIG.2B shows an instrument 199 with a detection element in the form of aballoon. Fluid (e.g., air, saline solution, or the like) can be usedinflate the balloon to evaluate airway attributes. The instrument 199can be a conventional instrument for airway dilation, airway occlusion,or the like. Instruments available for purchase from numerous medicalsuppliers, including Ackrad Laboratories, Cranford, N.J. and ErichJaeger, Hoechberg, Germany, can be used with, or modified to be usedwith, the treatments systems disclosed herein. The instruments can bedelivered through the treatment systems (e.g., through a central lumenof the treatment system) to position a detection element distal to thetreatment system.

The attributes of airways evaluated by the instrument may include,without limitation, physical properties of airways (e.g., airwaycompliance, contractile properties, etc.), airway resistance, dimensionsof airway lumens (e.g., shapes of airways, diameters of airways, etc.),responsiveness of airways (e.g., responsiveness to stimulation), musclecharacteristics (e.g., muscle tone, muscle tension, etc.), or the like.In some embodiments, changes of airway muscle characteristics can bemonitored by measuring pressure changes the intraluminal balloon that isinflated to a known pressure. Based on pressure changes in the balloon,a physician determines the effects, if any, of the treatment, including,without limitation, whether targeted tissue has been stimulated,damaged, ablated, or the like. For example, the balloon can bepositioned distal to the targeted tissue. As nerve tissue is damaged,muscle tension in the airway surrounding the balloon is reduced causingexpansion of the airway, as well as expansion of the balloon. Thepressure in the balloon decreases as the balloon expands.

The instrument 199 and the treatment system 198 can be delivered throughdifferent lumens in a delivery device, including, without limitation, amulti-lumen catheter, a delivery sheath, bronchoscope, an endoscope, orother suitable device for delivering and guiding multiple devices. Thedelivery device can be selected based on the location of the treatmentsite(s), configuration of the treatment system, or the like.

Decreases in airway resistance may indicate that passageways of airwaysare opening, for example, in response to attenuation of nervous systeminput to those airways. The decrease of airway resistance associatedwith treating low generation airways (e.g., main bronchi, lobar bronchi,segmental bronchi) may be greater than the amount of decrease of airwayresistance associated with treating high generation airways (e.g.,subsegmental bronchioles). A physician can select appropriate airwaysfor treatment to achieve a desired decrease in airway resistance and canbe measured at a patient's mouth, a bronchial branch that is proximateto the treatment site, a trachea, or any other suitable location. Theairway resistance can be measured before performing the therapy, duringthe therapy, and/or after the therapy. In some embodiments, airwayresistance is measured at a location within the bronchial tree by, forexample, using a vented treatment system that allows for respirationfrom areas that are more distal to the treatment site.

FIGS. 10A-14B illustrate treatment assemblies that can be generallysimilar to the treatment assembly 198A discussed in connection withFIGS. 5A-9, except as detailed below. FIG. 10A illustrates a treatmentsystem 198B that includes an elongate assembly 200B. The elongateassembly 200B includes an elongate flexible shaft 610 and a plurality ofradially deployable ablation assemblies 620. The ablation assemblies 620can be collapsed inwardly when the shaft 610 is pulled proximallythrough the delivery assembly 400 (shown in cross-section). When theplurality of ablation assemblies 620 is pushed out of the deliveryassembly 400, the ablation assemblies 620 self-expand by biasingradially outward.

Each electrode assembly 620 includes a sharp tip for piercing the airwaywall 103 and includes extendable and retractable sharp ablation elements625. The ablation assemblies 620 are preferably insulated except for theexposed ablation elements 625. The ablation assemblies 620 can beconnected to a RF electrical generator by electrical cables that travelwithin the shaft 610. While the treatment system 198B is beingdelivered, the ablation assemblies 620 may be positioned within theshaft 610. The ablation assemblies 620 can be moved out of the shaft 610and brought into contact with the wall 103. The ablation assemblies 620can be simultaneously moved through the airway wall 103 until desiredlengths of the ablation elements 625 are within the airway wall 103.

As shown in FIG. 10B, the plurality of ablation elements 625,illustrated as electrodes, may be circumferentially spaced from eachother along the airway wall 103. The ablation elements 625 can be evenlyor unevenly spaced from one another.

All of the ablation assemblies 620 can be connected to one lead of theRF generator and the other lead of the RF generator may be connected toan external electrode 623 (shown in phantom), so that current flowsbetween the ablation assemblies 620 and/or between one or more of theablation assemblies 620 and the external electrode 623. In someembodiments, a selected number of the ablation assemblies 620 areconnect to one lead of the RF generator while the other ablationassemblies 620 are connected to the other lead of the RF generator suchthat current flows between the ablation assemblies 620.

When the RF generator is activated, current flows through the tissue andgenerates a desired amount of heat. The heat can be concentrated on theoutside of the airway wall 103 to damage peripheral tissue. For example,the temperature of the connective tissue can be higher than thetemperatures of the stroma, smooth muscles, and/or the epithelium. Byway of example, the temperature of the connective tissue can besufficiently high to cause damage to the nerve tissues in the nervetrunks 45 while other non-targeted tissues of the airway 100 are kept ata lower temperature to prevent or limit damage to the non-targetedtissues. In other embodiments, heat can be concentrated in one or moreof the internal layers (e.g., the stroma) of the airway wall 103 or inthe inner periphery (e.g., the epithelium) of the airway wall 103.

As shown in FIG. 10B, one or more vessels of the bronchial arterybranches 130 may be relatively close to the ablation elements 625. Theheat generated by the ablation elements 625 can be controlled such thatthat blood flowing through the bronchial artery branches 130 protectsthe those branches 130 from thermal injury while nerve tissue isdamaged, even if the nerve tissue is next to the artery branches 130.Upon completion of the treatment process, the ablation assemblies 620are retracted back into the shaft 610 for removal from the airway 100 orfor placement at other treatment locations.

FIGS. 11A and 11B illustrate a treatment system 198C that includes anelongate assembly 200C. The elongate assembly 200C includes an elongateflexible shaft 710 and a plurality of extendable and retractableablation assemblies 720. When the ablation assemblies 720 are deployed,the ablation assemblies 720 bias radially outward and into contact witha tubular section 719 of the airway 100. Ablation elements 725 of theablation assemblies 720 can be axially and circumferentially distributedthroughout a treatment length L_(T) of the section 719.

The ablation assemblies 720 can include protective sections 721 and theexposed ablation elements 725. The protective sections 721 can extendfrom the shaft 710 to an inner surface of the airway 100. The ablationelements 725 protrude from corresponding protective sections 721. Theablation assemblies 720 can be connected to a radiofrequency (RF)electrical generator by electrical cables that travel within the shaft710.

The treatment system 198C is delivered to the desired treatment locationwithin the airway 100. While the treatment system 198C is beingdelivered, the ablation assemblies 720 are retracted within the shaft710 so as not to damage the airway 100 or the delivery device 400, orboth. Once in position, the sharp ablation elements 725 are brought intocontact with the airway wall 103. The elements 725 are then advancedthrough the airway wall 103 until the ablation elements 625 are embeddedwithin the airway wall 103. Substantially all of the ablation assemblies720 can be connected to one lead of the RF generator and the other leadof the RF generator may be connected to an external electrode, so thatcurrent flows between the ablation assemblies 720 and the externalelectrode. Alternatively, selected individual ablation assemblies 720can be connect to one lead of the RF generator while other ablationassemblies 720 can be connected to the other lead of the RF generator,so that current can flow between the ablation assemblies 720.

FIG. 12A illustrates the elongate assembly 200A of FIGS. 5A and 5Bpassing through a delivery assembly 400A, illustrated as a bronchoscope,that has an imaging device 850. The imaging device 850 is positioned ata tip 413A of the delivery assembly 400A. In some embodiments, theimaging device 850 includes an array of ultrasound transducers with aworking frequency between about 1 MHz to about 250 MHz and Dopplercapabilities. Wavefronts 860 outputted by the imaging device 850 areillustrated in FIGS. 12A and 12B.

When used, the delivery device 400A is advanced to the desired treatmentregion of the airway 100. The imaging device 850 is then used to imageat least a portion of the airway wall 103, thereby locating theanatomical structures, such as the nerve trunks 45 and/or bronchialartery branches 130, which are located in the connective tissue 124outside of the airway wall. For example, the imaging device 850 can beused to circumferentially image the airway 100. In some modes ofoperation, target tissues (e.g., the nerve trunks 45, mucous glands 116,and the like) are located such that only the portion of the wall 103immediately adjacent to the target tissues and the connective tissue 124are treated. In other modes of operation, the non-targeted tissues(e.g., bronchial artery branches 130) are localized and all otherregions of the wall 103 and the connective tissue 124 are treated.

When treating the nerve trunks 45, the tip 413 of the delivery device400A can be guided and positioned near a selected nerve trunk 45. Oncein position, the sharp ablation element 525 is brought into contact withthe wall 103. The ablation element 525 is then advanced through the wall103 until the ablation elements 525 are embedded. The illustratedexposed ablation elements 525 are adjacent to the nerve trunk in theconnective tissue 124. The RF generator is activated and current flowsbetween the ablation assembly 520 and the tissue of the wall 103. Thecurrent causes the tissues of the nerve trunks 45 to increase intemperature until the heated tissue is damaged. By positioning theablation assembly 520 near the nerve trunk 45, the nerve trunk 45 isselectively damaged while injury to non-targeted tissues, such as thebronchial arteries 130, is minimized. This procedure may be repeated todamage additional nerve branches 45 located around the circumference ofthe wall 103 in or adjacent to the connective tissue 124.

Various types of devices can be used to remotely treat target tissues.FIGS. 13A and 13B illustrate a treatment system 200E in the form of abronchoscope having high energy ultrasound transducer array 950 locatedat its tip 413E. The energy ultrasound transducer array 950 can bepositioned to image the desired treatment site. The ultrasoundtransducer array 950 is then used to circumferentially image the wall103 to localize the nerve trunks 45 and/or the bronchial arteries 130.In some modes of operation, the nerve trunks 45 are localized and onlythe area of the wall 103 of the airway 100 and the connective tissue 124around the nerve trunks 45 is treated using ultrasound energy. In othermodes of operation, the bronchial arteries 130 are localized and allother areas of the wall 103 of the airway 100 and the connective tissue124 are treated using ultrasound energy.

The ultrasound transducer array 950 can emit highly focused sound waves960 into the connective tissue 124 to damage the nerve trunks 45 andminimize or prevent injury to the bronchial arteries 130. The tip 413Eof the bronchoscope 400B can be positioned such that the outputtedenergy is directed away from or does not reach the bronchial arterybranches 130. This procedure of remotely treating tissue may be repeatedto damage additional nerve trunks 45 located around the circumference ofthe wall 103 in the connective tissue 124, as desired. The bronchoscope400B can be used to damage all or at least some of the nerve trunks 45at a particular section of the airway 100.

FIGS. 14A and 14B illustrate a treatment system 198F that includes anelongate assembly 200F. The elongate assembly 200F includes an elongatedshaft 1110 and an extendable and retractable puncturing tip 1120. Thepuncturing tip 1120 is adapted to pass through tissue and includes atleast one port 1130. The illustrated puncturing tip 1120 includes asingle side port 1130 for outputting flowable substances. A lumen canextend proximally from the port 1130 through the shaft 1110. A flowablesubstance can flow distally through the lumen and out of the port 1130.Example flowable substances include, without limitation, one or moreheated liquids, cooled liquids, heated gases, cooled gases, chemicalsolutions, drugs, and the like, as well as other substances that thatcan cause damage to tissue. For example, saline (e.g., heated or cooledsaline) or cryogenic fluids can be delivered through the port 1130.

The elongate assembly 200F of FIGS. 14A and 14B can be delivered to thedesired treatment location using the delivery assembly 400. While theelongate assembly 200F is being delivered, the puncturing tip 1120 isretracted within the shaft 1110 so as to not damage the airway 100and/or the delivery assembly 400. Once in position, the sharp hollow tip1020 is brought into contact with the airway wall 103. The tip 1020 isthen advanced through the airway wall 103 until the side port 1130 iswithin or adjacent to the connective tissue 124. The flowable substanceis delivered through the tip 1020 and out of the port 1130 and flowsagainst the tissue of the airway 100. In some embodiments, the expelledsubstance cuts, crushes, or otherwise damages the tissue. In someembodiments, the flowable substance includes at least one long actingnerve blocking drug that partially or completely blocks nerve conductionin the nerve trunks 45.

FIGS. 15A-19B illustrate treatment systems that can be generally similarto the treatment system 198A discussed in connection with FIGS. 5A-9,except as detailed below. FIG. 15A is a longitudinal side view of atreatment system 2000 in the form of a balloon expandable, fluidheated/cooled electrode catheter. FIG. 15B is a cross-sectional view ofan expandable assembly 2001 of the system 2000. The illustratedexpandable assembly 2001 is in an expanded state. Lines of flow 2100represent the movement of fluid through the expanded assembly 2001. Theexpanded assembly 2001 includes an expandable member 2002 and anablation electrode 2004. The ablation electrode 2004 can be collapsedinwardly when the treatment system 2000 is moved (e.g., pulledproximally or pushed distally) through a delivery assembly. When thetreatment system 2000 is pushed out of the delivery assembly, theablation electrode 2004 can be expanded outward by inflating theexpandable member 2002.

The treatment system 2000 generally includes the expandable member 2002(illustrated in the form of a distensible, thermally conductiveballoon), an ablation electrode 2004, a conducting element 2031, aninflow line 2011, and an outflow line 2021. The ablation electrode 2004is expandable and connected to a distal end 2033 of the conductingelement 2031. A proximal end 2035 of the conducting element 2031 isconnected to an electrical connector 2038. Energy is transferred fromthe electrical connector 2038 to the expandable electrode 2004 throughthe conducting element 2031. The conducting element 2031 can include,without limitation, one or more wires, conduits, or the like.

A proximal end 2009 of the inflow line 2011 has an inline valve 2012. Aproximal end 2015 of the outflow line 2021 also has an outflow valve2022. The inline valve 2011 can be connected to a fluid supply, such asa coolant source, by a connector 2018. Fluid flows through the inflowline 2011 into the balloon 2002, and exits the balloon 2002 via theoutflow line 2021. The fluid can include, without limitation,temperature controlled fluid, such as water, saline, or other fluidsuitable for use in a patient.

A lumen 2017 of the inflow line 2011 and a lumen 2019 of the outflowline 2021 provide fluid communication with the balloon 2002. Fluid canflow through the lumen 2017 into the balloon 2002. The fluid circulateswithin the balloon 2002 and flows out of the balloon 2002 via the lumen2019. The fluid can pass through the connector 2028 to a fluid returnsystem, which may cool the fluid and re-circulate the fluid to the fluidsupply.

Different types of materials can be used to form different components ofthe system 2000. In some embodiments, the balloon 2002 is made, in wholeor in part, of a distensible, chemically inert, non-toxic, electricallyinsulating, and thermally conductive material. For example, the balloon2002 may be made of polymers, plastics, silicon, rubber, polyethylene,combinations thereof, or the like. In some embodiments, the inflow line2011 and the outflow line 2021 are made, in whole or in part, of anysuitable flexible, chemically inert, non-toxic material for withstandingoperating pressures without significant expansion. The inflow line 2011and the outflow line 2021 can have a suitable length to be passed intothe lung and bronchial tree. For example, the lines 2011, 2021 can havea length of approximately 80 cm. Other lengths are also possible.

FIG. 15B shows the inflow line 2011 and the outflow line 2021 arrangedto minimize, reduce, or substantially prevent cross flow, siphoning, orback flow between the two lines 2011, 2021. The illustrated inflow line2011 carries the balloon 2004. The inflow line 2011 can enter a proximalend 2003 of the balloon 2002, extend through the length of the balloon2002, and reach a distal end 2007 of the balloon 2002. The illustratedinflow line 2011 is connected to the distal end 2007 to keep the balloon2002 in an elongated configuration.

A tip 2005 protrudes from the balloon 2002. The illustrated tip 2005 isan atruamatic tip positioned opposite the end of the inflow line 2011.Near the tip 2005, the inflow line 2011 has an aperture 2013 thatreleases fluid into the balloon 2002. The fluid flows within the balloon2002 and is collected into the outflow line 2021. The illustratedoutflow line 2021 has an opening 2023 for receiving the fluid. Theopening 2023 is generally at the distal end of a portion of the outflowline 2021 in the balloon 2002 and collects fluid from any direction.Because the openings 2013, 2023 are at opposite ends of the balloon2002, fluid can flow in generally one direction through the balloon2002. This ensures that fluid at a desired temperature fills the balloon2002.

The shapes of the electrode 2004 and the balloon 2002 can be selectedsuch that the electrode 2004 and balloon 2004 expand/deflate together.When the balloon 2002 is inflated, the electrode 2004 is expanded withthe balloon 2002. When the balloon 2002 is deflated, the electrode 2004contracts with the balloon 2002. The electrode 2004 may be coupled to anexterior surface or interior surface of the balloon 2002 and may be madeof different types of conductive materials, including, withoutlimitation, any chemically inert, non-toxic, structurally resilient,electrically conducting material. In some embodiments, the electrode2004 is coupled to the exterior of the balloon 2002 and made, in wholeor in part, of a highly conductive, deformable material. Energyoutputted by the electrode 2004 is outputted directly into the airwaywall 100 without passing through the wall of the balloon 2002. Theelectrode 2004 can be a thin wire or band made mostly or entirely ofcopper. The wire can be coated or uncoated depending on the application.In other embodiments, the electrode 2004 is embedded in the wall of theballoon 2002. Any number of electrodes 2004 can be positioned along theballoon 2002. For example, an array of spaced apart electrodes can bepositioned along the balloon to treat a length of an airway.

The electrical conducting element 2031 travels along side and generallyparallel to one or both of the lines 2011, 2021. The electrode 2004 canbe connected through the electrical conducting element 2031 and theelectrical connector 2038 to an energy source, such as an RF electricalgenerator. If the energy source is an RF electrical generator, one leadcan be coupled to the connector 2038. The other lead of the RF generatormay be connected to an external electrode, such as the externalelectrode 623 shown in phantom in FIG. 10B, so that current flowsbetween the expandable electrode 2004 and the external electrode.

The balloon expandable, fluid cooled electrode catheter 2000 can bedelivered into the airways of the lung with the balloon 2002 deflatedand the electrode 2004 contracted. The electrode 2004 can be kept in acollapsed or closed configuration to allow the catheter 2000 to passeasily through the lungs. The catheter 2000 is moved through the airwaysuntil the electrode 2004 is at the desired treatment location. Once inposition, fluid (e.g., coolant) is allowed to flow through the inflowline 2011 and into the balloon 2002. The fluid inflates the balloon 2002which in turn expands the electrode 2004. Outflow of the fluid throughthe outflow line 2021 can be regulated such that the balloon 2002continues to inflate until the electrode 2004 is brought into contactwith or proximate to the airway wall.

Treatment can begin with activation of the RF generator. When the RFgenerator is activated, RF energy is transmitted through the electricalconnector 2038, through the electrical connection element 2031, throughthe expanded electrode 2004, and into the tissues of the airways. The RFenergy heats tissue (e.g., superficial and deep tissue) of the airwaywall and the fluid 2100 (e.g., a coolant) flowing through the balloon2002 cools tissue (e.g., superficial tissues) of the airway wall. Thenet effect of this superficial and deep heating by RF energy andsuperficial cooling by the circulating coolant 2100 through the balloon2002 is the concentration of heat in the outer layers of the airway wall100. The coolant can be a chilled liquid. The temperature of theconnective tissue can be higher than the temperatures of the epithelium,stroma, and/or smooth muscle. By example, the temperature of theconnective tissue can be sufficiently high to cause damage to the nervetrunk tissue while other non-targeted tissues of the airway are kept ata lower temperature to prevent or limit damage to the non-targetedtissues. In other embodiments, heat can be concentrated in one or moreof the internal layers (e.g., the stroma) of the airway wall or in theinner lining (e.g., the epithelium) of the airway wall.

FIGS. 16 and 17 show the effect produced by superficial and deep heatingby RF energy and superficial cooling by circulating coolant 2100 in theballoon 2002. FIG. 16 shows a cross-sectional temperature profile takenalong a dashed line 2200 of FIG. 15B that is perpendicular to the longaxis of the balloon 2002. FIGS. 16 and 17 are discussed in detail below.

FIG. 16 is a graph with a horizontal axis corresponding to the depthinto the tissue of the airway wall from the point of contact or area ofcontact with the electrode 2004 in millimeters with a vertical axiscorresponding to the temperature of the tissue in degrees Centigrade.The point “0” on the graph corresponds to the point or area of contactbetween the ablation electrode 2004 and the tissue of the airway wall.Three curves A, B, and C are shown in the graph and correspond to threedifferent power levels of radio frequency energy being delivered intothe tissue. The temperature on the graph is up to about 100° C. Thetemperature of about 100° C., or slightly less, has been shown becauseit is considered to be an upper limit for tissue temperature during RFablation. At approximately 90° C., tissue fluids begin to boil andtissue coagulates and chars on the ablation electrode 2004, therebygreatly increasing its impedance and compromising its ability totransfer RF energy into the tissue of the airway wall. Thus, it may bedesirable to have tissue temperatures remain below about 90° C. At about50° C., a line 2201 represents the temperature above which tissue celldeath occurs and below which tissues suffer no substantial long termeffects (or any long term effects).

Curve A shown in FIG. 16 represents what occurs with and without coolingof the ablation electrode 2004 at a relatively low power level, forexample, about 10 watts of RF energy. Curve A is divided into threesegments A1, A2, and A3. The broken line segment A2 represents acontinuation of the exponential curve A3 when no cooling applied. As canbe seen by curve A, the temperature of the electrode-tissue interfacewithout cooling reaches 80° C. and decreases exponentially as thedistance into the tissue of the airway 100 increases. As shown, thecurve A3 crosses the 50° C. tissue cell death boundary represented bythe line 2201 at a depth of about 5 millimeters. Thus, without electrodecooling, the depth of cell death that would occur would be approximately5 millimeters as represented by the distance d1. Further cell deathwould stop at this power level.

If active cooling is employed, the temperature drops to a much lowerlevel, for example, about 35° C. as represented by the curve A1 at theelectrode-tissue interface at 0 millimeters in distance. Since thistemperature is below 50° C., cell death will not begin to occur until adistance of d2 at the point where the curve A2 crosses the cell deathline at 50° C., for example, a depth of 3 millimeters from the surface.Cell death will occur at depths from 3 millimeters to 5 millimeters asrepresented by the distance d3. Such a cooled ablation procedure isadvantageous because it permits cell death and tissue destruction tooccur at a distance (or a range of distances) from the electrode-tissueinterface without destroying the epithelium and the tissue immediatelyunderlying the same. In some embodiments, the nerve tissues runningalong the outside of the airway can be ablated without damaging theepithelium or underlying structures, such as the stroma and smoothmuscle cells.

The curve B represents what occurs with and without cooling of theelectrode at a higher power level, for example, 20 watts of RF energy.Segment B2 of curve B represents a continuation of the exponential curveof the segment B3 without cooling. As can be seen, the temperature atthe electrode-tissue interface approaches 100° C. which may beundesirable because that is a temperature at which boiling of tissuefluid and coagulation and charring of tissue at the tissue-electrodeinterface will occur, thus making significantly increasing the tissueimpedance and compromising the ability to deliver additional RF energyinto the airway wall. By providing active cooling, the curve B1 showsthat the temperature at the electrode-tissue interface drops toapproximately 40° C. and that cell death occurs at depths of twomillimeters as represented by d4 to a depth of approximately 8millimeters where the curve B3 crosses the 50° C. Thus, it can be seenthat it is possible to provide a much deeper and larger region of celldeath using the higher power level without reaching an undesirable hightemperature (e.g., a temperature that would result in coagulation andcharring of tissue at the electrode-tissue interface). The systems canbe used to achieve cell death below the epithelia surface of the airwayso that the surface need not be destroyed, thus facilitating earlyrecovery by the patient from a treatment.

The curve C represents a still higher power level, for example, 40 wattsof RF energy. The curve C includes segments C1, C2, and C3. The brokenline segment C2 is a continuation of the exponential curve C3. SegmentC2 shows that the temperature at the electrode-tissue interface farexceeds 100° C. and would be unsuitable without active cooling. Withactive cooling, the temperature at the electrode-tissue interfaceapproaches 80° C. and gradually increases and approaches near 95° C. andthen drops off exponentially to cross the 50° C. cell death line 2201 ata distance of about 15 millimeters from the electrode-tissue interfaceat the epithelial surface of the airway represented by the distance d6.Because the starting temperature is above the 50° C. cell death line2201, tissue cell death will occur from the epithelial surface to adepth of about 15 millimeter to provide large and deep regions of tissuedestruction.

FIG. 17 is a longitudinal cross-sectional view of the balloonexpandable, fluid cooled electrode catheter 2000. Lines of flow 2100represent the movement of coolant through the expanded balloon 2002.Isothermal curves show the temperatures that are reached at theelectrode 2004 on the outer surface of the balloon 2002 and at differentdepths into the airway wall 100 from the electrode-tissue interface whenpower is applied to the electrode 2004 and coolant (e.g., a roomtemperature saline solution) is delivered to the balloon 2002. Byadjusting the rate of power delivery to the electrode 2004, the rate atwhich saline solution is passed into the balloon 2002, the temperatureof the saline solution, and the size of the balloon 2002, the exactcontour and temperature of the individual isotherms can be modified. Forexample, by selecting the proper temperature and flow rate of saline andthe rate of power delivery to the electrode, it is possible to achievetemperatures in which isotherm A=60° C., B=55° C., C=50° C., D=45° C.,E=40° C., and F=37° C. Further adjustments make it possible to achievetemperatures where isotherm A=50° C., B=47.5° C., C=45° C., D=42.5° C.,E=40° C., and F=37° C. Only those areas contained within the 50° C.isotherm will be heated enough to induce cell death. Extrapolating into3 dimensions the isotherms shown in FIG. 17, a circumferential band 2250of tissue will potentially be heated above 50° C. sparing the tissuenear the epithelial 110 of the airway 100. Different temperatures andisotherms can also be achieved.

FIG. 18 is a transverse cross-sectional view of a portion of the airway100 and the balloon expandable, fluid cooled electrode catheter 2000positioned in the airway 100. Because of the undulating shape of theexpandable electrode 2004, the electrode appears as a multitude ofovals. The balloon 2002 is inflated to conform to both the expandableelectrode 2004 and the epithelial surface of the airway 100. Theelectrode 2004 can be pressed against the airway 100. When RF energy istransmitted through the expanded electrode 2004 into the tissues of theairway 100 and the balloon 2002 is filled with flowing coolant 2100, theRF energy heats the superficial and deep tissue of the airway wall 100and the connective tissue 124 while the coolant 2100 cools thesuperficial tissues of the airway wall 100. The net effect of thissuperficial and deep heating by RF energy and superficial cooling by thecirculating coolant 2100 is the concentration of heat in the outerlayers of the airway wall 100, such as the connective tissue 124. A band2250 of tissue can be selectively heated above 50° C. For example, thetemperature of the connective tissue 124 can be higher than thetemperatures of the epithelium 110, stroma 112, and/or smooth muscle114. Furthermore, one or more of the vessels of the bronchial arterybranches 130 may be within the band 2250. The heat generated using theelectrode 2004 can be controlled such that blood flowing through thebronchial artery branches 130 protects those branches 130 from thermalinjury while nerve trunk tissue 45 is damaged, even if the nerve tissueis next to the artery branches.

The electrode catheter 2000 can treat tissue without forming an airwaywall perforation at the treatment site to prevent or reduce thefrequency of infections. It may also facilitate faster healing for thepatient of tissue proximate the region of cell death. The catheter 2000can produce relatively small regions of cell death. For example, a 2 to3 millimeter band of tissue in the middle of the airway wall 100 oralong the outer surface of the airway wall 100 can be destroyed. By theappropriate application of power and the appropriate removal of heatfrom the electrode, lesions can be created at any desired depth withoutdamaging the inner surface of the airway.

Upon completion of the treatment process, coolant inflow into theballoon 2002 can be stopped. The balloon 2002 is deflated causing theexpandable electrode 2004 to recoil away from the airway wall 100. Whenthe balloon 2002 is completely deflated, the balloon expandable, fluidcooled electrode catheter 2000 may be repositioned for treating otherlocations in the lung or removed from the airway 100 entirely.

FIGS. 19A and 19B illustrate a treatment system that can be generallysimilar to the catheter 2000 discussed in connection with FIGS. 15A-18.A balloon expandable, fluid heat-sink electrode catheter 2500 has asingle coolant line 2511 with associated inline valve 2512 and connector2518 that provide for alternately inflow and outflow of heat-sink fluidinto and out of a balloon 2502.

The balloon expandable, fluid heat-sink electrode catheter 2500 can bedelivered into the airways of the lung with the balloon 2502 deflatedand the electrode 2504 contracted. The catheter 2500 can be moved withinthe airways until the electrode 2504 is in a desired treatment location.Once in position, heat-sink fluid is passed through the line 2511 andinto the balloon 2502, thereby inflating the balloon 2502 and expandingthe electrode 2504. The fluid is passed into the balloon 2502 until theelectrode 2504 is brought into contact with the airway wall 100.

The heat-sink fluid passed into the balloon 2502 of electrode catheter2500 is generally static and acts as a heat-sink to stabilize thetemperature of the electrode 2504 and the superficial tissues of theairway wall 100. The static heat sink provided by the fluid in theballoon 2502 can produce temperature profiles and isotherms similar tothose shown in FIGS. 16 and 17. For example, the electrode catheter 2500can cause a band of tissue cell death in the connective tissue of theairway while the epithelium, stroma, and/or smooth muscle are relativelyundamaged. Thus, the nerve tissue can be damaged while othernon-targeted tissues of the airway are protected.

FIGS. 20A-21 illustrate a treatment system that can be generally similarto the balloon expandable, fluid cooled electrode catheter 2000 shown inFIGS. 15A-18. FIG. 20A is a longitudinal side view of a radialultrasound guided fluid cooled electrode catheter 3000. FIG. 20B is apartial longitudinal sectional view of the radial ultrasound guidedfluid cooled electrode catheter 3000 taken through a balloon 3002 withlines of flow 3100 representing the movement of coolant through theexpanded balloon 3002 and wavefronts 3047 of ultrasound imaging forguiding the ablation device.

The electrode catheter 3000 generally includes a distensible, thermallyconductive balloon 3002, an electrode 3004, a conducting element 3031,an inflow line 3011, an outflow line 3021, and an ultrasound probe 3045.The expandable electrode 3004 is connected to a distal end of theconducting element 3031. A proximal end of the conducting element 3031is connected to an electrical connector 3038 for transmission of energy(e.g., RF energy) to the electrode 3004. The proximal end of the coolantinflow line 3011 has an inline valve 3012. The proximal end of thecoolant outflow line 3021 also has an outline valve 3022. The inflowvalve 3012 can be connected to a coolant source by the connector 3018.The lumen of the inflow line 3011 and the lumen of the outflow line 3021provide for fluid to flow from the fluid source to the inside of theballoon 3002 and for fluid flow through another connector 3028 to thecoolant return, where the coolant may be re-cooled and re-circulated tothe fluid supply.

The inflow line 3011 and outflow line 3021 have a suitable length to bepassed into the lung and bronchial tree. For example, the catheter 3000can have a length of approximately 80 cm. FIG. 20B shows a catheter 3000is adapted to reduce, limit, or substantially prevent cross-flow,siphoning, or back-flow between the two lines within the balloon 3002.The inflow line 3011 enters the proximal end of the balloon 3002,extends through the length of the balloon 3002, reaches the distal endof the balloon 3002, and connects to the balloon 3002. The inflow line3011 has an aperture 3013 near a tip 3005 that releases coolant into theballoon 3002. The fluid flows within the balloon 3002 and then iscollected into the outflow line 3021 via an opening 3023. The opening3023 is generally at the distal end of the outflow line 3021 andcollects coolant from any direction.

The electrode 3004 is located on a surface of the balloon 3002 suchthat, when the balloon 3002 is inflated using fluid, the electrode 3004is brought into contact with the airway wall 100. The electricalconducting element 3031 travels along side and parallel to the inflowline 3011, the outflow line 3021, and the ultrasound sheath 3041. Theelectrode 3004 can be connected through the electrical conductingelement 3031 and the electrical connector 3038 to an RF generator. Theother lead of the RF generator may be connected to an external electrodeso that current flows between the expandable electrode 3004 and theexternal electrode.

The ultrasound probe 3045 may be an integral part of the ultrasoundguided fluid cooled electrode catheter 3000 or it may be a separate,standard radial ultrasound probe, such as an Olympus UM-2R-3 or UM-3R-3probe driven by a standard Olympus processor EU-M60, with the radialultrasound guided fluid cooled electrode catheter 3000 configured toslip over the standard radial ultrasound probe.

The ultrasound system can include a broadband ultrasound transduceroperating with a center frequency between about 7 MHz and about 50 MHz.If the ultrasound probe 3045 is an integral part of the electrodecatheter 3000, the ultrasound probe 3045 may be contained within anacoustically matched ultrasound cover 3041 and connected to anultrasound drive unit and processor by the ultrasound connector 3048. Inoperation, the ultrasound probe 3045 is rotated about its longitudinalaxis within the ultrasound cover 3041 by the ultrasound drive unit andprocessor through the ultrasound connector 3048 allowing images (e.g.,360° radial images) to be taken. These images can be taken in adirection perpendicular to the long axis of the ultrasound probe 3045.The fluid in the balloon 3002 can acoustically couple the ultrasoundprobe 3045 to the airway wall.

The electrode catheter 3000 can be delivered into the airways of thelung with the balloon 3002 in a deflated state. The catheter 3000 ispositioned within the airways near or at the desired treatment location.Once positioned, fluid flows through the inflow line 3011 and into theballoon 3002. The balloon 3002 inflates to bring the electrode 3004 intocontact with the epithelial surface of the airway. Outflow of fluidthrough the outflow line 3021 can be regulated such that the balloon3002 continues to inflate until the electrode 3004 is brought intocontact with the airway wall 100.

The ultrasound drive unit and processor can be activated. The ultrasoundprobe 3045 can capture images. For example, the probe 3045, within theultrasound cover 3041, can be rotated about its longitudinal axis toproduce 360° radial images of the airway and vessels airway wallstructures. The electrical connection wire 3031 can serve as a guide onthe ultrasound images to the location of the electrode 3004. A sectionof the wire 3031 extending along (e.g., over the surface) of the balloon3002 can be visible in the ultrasound images. The section of wire 3031can therefore indicate the location of the electrode 3004. In someembodiments, the nerve trunks and bronchial blood can be identified inthe ultrasound images and the ultrasound guided fluid cooled electrodecatheter 3000 can be rotated until the electrode 3004 is brought intoproximity with the first nerve trunk 45.

When the RF generator is activated, RF energy is transmitted by thegenerator through the electrical connector 3038, through the electricalconnection wire 3031, through the expanded electrode 3004, and into thetissues of the airways. The RF energy heats the superficial and deeptissue of the airway wall 100 and the connective tissue 124 in the areaimmediately overlying the electrode 3004 and the coolant flowing 3100through the balloon 3002 cools the superficial tissues of the airwaywall 100. The net effect of this superficial and deep heating by RFenergy and superficial cooling by the circulating coolant 3100 throughthe balloon 3002 is the concentration of heat in the outer layers of theairway wall 100 immediately overlying the electrode 3004. For example,the temperature of the connective tissue 124 in the area of a singlenerve trunk 45 can be higher than the temperatures of the epithelium110, stroma 112, and/or smooth muscle 114. By example, the temperatureof the connective tissue can be sufficiently high to cause damage to thenerve tissue 45 while other non-targeted tissues of the airway 100 arekept at a lower temperature to prevent or limit damage to thenon-targeted tissues. The treatment can be repeated in other areas asneeded.

FIG. 21 is a transverse cross-sectional view of a portion of the airway100 and the ultrasound guided fluid cooled electrode catheter 3000positioned in the airway 100. The cross-section is taken through theelectrode 3004 itself.

The balloon 3002 is conformable to both the electrode 3004 and theepithelial surface of the airway 100. When RF energy is transmittedthrough the electrode 3004 into the tissues of the airways and theballoon 3002 is filled with flowing coolant 3100, the RF energy heatsthe superficial and deep tissue of the airway wall 100 immediatelyoverlying the electrode 3004. The coolant 3100 flows to control thetemperature of the superficial tissues of the airway wall 100. The neteffect is the concentration of heat in the outer layers of the airwaywall 100 immediately over the electrode 3004 producing a single targetvolume 3250 of tissue heated above a treatment temperature (e.g., about50° C.). For example, the temperature of the connective tissue 124 inthe region of a single nerve trunk 45 in the region immediately over theelectrode 3004 can be higher than the temperatures of the epithelium110, stroma 112, and/or smooth muscle 114.

The vessels of the bronchial artery branches 130 may be within or nearthe volume of heating produced during application of RF energy. The heatgenerated by the electrode 3004 can be controlled such that bloodflowing through the bronchial artery branches 130 protects thosebranches 130 from thermal injury while nerve tissue 45 is damaged, evenif the nerve tissue is next to the artery branches.

The embodiments disclosed herein can be used in the respiratory system,digestive system, nervous system, vascular system, or other systems. Forexample, the elongate assemblies disclosed herein can be deliveredthrough blood vessels to treat the vascular system. The treatmentsystems and its components disclosed herein can used as an adjunctduring another medical procedure, such as minimally invasive procedures,open procedures, semi-open procedures, or other surgical procedures(e.g., lung volume reduction surgery) that preferably provide access toa desired target site. Various surgical procedures on the chest mayprovide access to lung tissue. Access techniques and procedures used toprovide access to a target region can be performed by a surgeon and/or arobotic system. Those skilled in the art recognize that there are manydifferent ways that a target region can be accessed.

The elongated assemblies disclosed herein can be used with guidewires,delivery sheaths, optical instruments, introducers, trocars, biopsyneedles, or other suitable medical equipment. If the target treatmentsite is at a distant location in the patient (e.g., a treatment sitenear the lung root 24 of FIG. 1), a wide range of instruments andtechniques can be used to access the site. The flexible elongatedassemblies can be easily positioned within the patient using, forexample, steerable delivery devices, such as endoscopes andbronchoscopes, as discussed above.

Semi-rigid or rigid elongated assemblies can be delivered using trocars,access ports, rigid delivery sheaths using semi-open procedures, openprocedures, or other delivery tools/procedures that provide a somewhatstraight delivery path. Advantageously, the semi-rigid or rigidelongated assemblies can be sufficiently rigid to access and treatremote tissue, such as the vagus nerve, nerve branches, nerve fibers,and/or nerve trunks along the airways, without delivering the elongatedassemblies through the airways. The embodiments and techniques disclosedherein can be used with other procedures, such as bronchialthermoplasty.

The various embodiments described above can be combined to providefurther embodiments. These and other changes can be made to theembodiments in light of the above-detailed description. The embodiments,features, systems, devices, materials, methods and techniques describedherein may, in some embodiments, be similar to any one or more of theembodiments, features, systems, devices, materials, methods andtechniques described in of U.S. Provisional Patent Application No.61/052,082 filed May 9, 2008; U.S. Provisional Patent Application No.61/106,490 filed Oct. 17, 2008; and U.S. Provisional Patent ApplicationNo. 61/155,449 filed Feb. 25, 2009. In addition, the embodiments,features, systems, devices, materials, methods and techniques describedherein may, in certain embodiments, be applied to or used in connectionwith any one or more of the embodiments, features, systems, devices,materials, methods and techniques disclosed in the above-mentioned ofU.S. Provisional Patent Application No. 61/052,082 filed May 9, 2008;U.S. Provisional Patent Application No. 61/106,490 filed Oct. 17, 2008;and U.S. Provisional Patent Application No. 61/155,449 filed Feb. 25,2009. Each of these applications is hereby incorporated by reference inits entirety. In general, in the following claims, the terms used shouldnot be construed to limit the claims to the specific embodimentsdisclosed in the specification and the claims, but should be construedto include all possible embodiments along with the full scope ofequivalents to which such claims are entitled. Accordingly, the claimsare not limited by the disclosure.

What is claimed is:
 1. A method of treating a subject comprising:positioning a treatment device at a treatment site within a first airwayof the subject, wherein at least one nerve trunk runs along the firstairway and carries nervous system signals to or from a second airwaythat is a higher generation airway of the first airway; and damaging thenerve trunk using the treatment device sufficiently to inhibittransmission of the nervous system signals past the treatment site suchthat airway resistance in the higher generation airway is reduced. 2.The method of claim 1 wherein the nerve trunk is closer to an exteriorsurface of an airway wall of the first airway than to an interiorsurface of the airway wall of the first airway.
 3. The method of claim 1wherein the nerve trunk is disposed along an exterior surface of anairway wall of the first airway.
 4. The method of claim 1 wherein thenerve trunk is radially outside a smooth muscle layer of the firstairway.
 5. The method of claim 1 further comprising inhibiting damage toairway tissue disposed radially between the treatment device and thenerve trunk.
 6. The method of claim 5 wherein the inhibiting damage stepcomprises cooling the airway tissue using the treatment device.
 7. Themethod of claim 6 wherein the cooling step comprises absorbing heat fromthe airway tissue with a cooling element on the treatment device.
 8. Themethod of claim 6 wherein the treatment device comprises an energyemitter for delivering energy to the nerve trunk.
 9. The method of claim1 wherein the airway resistance in the higher generation airway isreduced without delivering energy in the higher generation airway. 10.The method of claim 1 wherein the first airway is between a trachea anda lung of the subject.
 11. The method of claim 10 wherein the firstairway comprises a left or right main bronchus or a bronchusintermedius.
 12. The method of claim 1 wherein the first airway is afirst generation airway located outside of the left and right lungs. 13.The method of claim 1 wherein airway resistance in the higher generationairway is reduced by reducing airway inflammation in the highergeneration airway.
 14. A method of treating a subject comprising:delivering energy so as to damage nerve tissue at a first site along afirst airway of the subject such that nervous system signals travelingthrough the nerve tissue are blocked sufficiently to reduce airwayresistance in a second airway that is a higher generation airway of thefirst airway.
 15. The method of claim 14 wherein the nerve tissue iscloser to an exterior surface of a wall of the first airway than to aninterior surface of the wall of the first airway.
 16. The method ofclaim 14 wherein the nerve tissue is disposed along an exterior surfaceof a wall of the first airway.
 17. The method of claim 14 wherein thenerve tissue is radially outside a smooth muscle layer of the firstairway.
 18. The method of claim 14 wherein the nerve tissue is damagedusing a treatment device positioned in the first airway, the methodfurther comprising inhibiting damage to airway tissue disposed radiallybetween the treatment device and the nerve tissue.
 19. The method ofclaim 18 wherein the inhibiting damage step comprises cooling the airwaytissue using the treatment device.
 20. The method of claim 19 whereinthe cooling step comprises absorbing heat from the airway tissue with acooling element on the treatment device.
 21. The method of claim 19wherein the treatment device comprises an energy emitter for deliveringenergy to the nerve tissue.
 22. The method of claim 14 wherein the firstairway is between a trachea and a lung of the subject.
 23. The method ofclaim 22 wherein the first airway comprises a left or right mainbronchus or a bronchus intermedius.
 24. The method of claim 14 whereinthe first airway is a first generation airway located outside of theleft and right lungs.
 25. The method of claim 14 wherein airwayresistance in the higher generation airway is reduced by reducing airwayinflammation in the higher generation airway.